This proposal describes a five year mentored training program for the development of an academic career as a clinician scientist in biomedical research with a focus on the developmental biology of kidney branching morphogenesis. The principal investigator (PI), who holds an M.D. degree, is residency-trained in Internal Medicine and Nephrology. The PI has already initiated research on ureteric bud (UB) branching morphogenesis in the laboratory of Dr. Sanjay Nigam, the proposed mentor, at the University of California, San Diego (UCSD). Dr. Nigam is a distinguished Physician-Scientist who has authored numerous influential studies on the cellular and molecular biology of kidney development. The program will incorporate formal didactics as well as research training to enhance the PI's skills in the areas of cell biology, developmental biology, glycobiology, and bioengineering. The PI's research will focus on the role of heparan sulfate (HS) in UB branching morphogenesis. Variably sulfated HS chains play a role in branching through their multiple interactions with growth factors. As such, it is likely that HS is significantly involved in kidney organogenesis through the regulation growth factor mediated growth and patterning of the ureteric tree. Perturbation of HS therefore likely contributes to the pathogenesis of overt developmental disorders (renal agenesis) or more subtle defects such as diminished nephron number, which is associated with hypertension. This proposal aims to elucidate the role of HS sulfation pattern in ureteric branching. The specific aims are as follows: (1) We will characterize endogenous HS and HS biosynthetic enzyme expression during ureteric bud branching morphogenesis using in vitro models. (2) We will test the hypothesis that perturbation of fine HS sulfation pattern affects branching tubulogenesis of kidney epithelial cells and in vitro models of kidney develpment. (3) We will use transgenic mice to study the effect of selective HS perturbation on in vitro branching morphogenesis using adeno-Cre inactivation of floxed genes in kidney rudiments.